Reform of the first year of medical studies and diversification of student profiles in France: an unmet need?

OBJECTIVES: To determine whether the reform of the first year of medical studies implemented in September 2020 in France met its objective of diversifying the profiles of students admitted to second year at the faculty of medicine at the University of Tours. METHODS: Single-centered, retrospective study, covering students who passed the first year of medical studies between 2018 and 2022. Student profiles originating from three different entry gateways (PACES, PASS and L.AS) to the second year of medical studies were compared. RESULTS: One thousand four hundred and seventy-nine students over five promotions were included (806 in PACES, 329 in PASS, 198 in L.AS). The ratio of students who had obtained a baccalaureate with high or highest honors was significantly higher in PACES (85%) and PASS (96%) compared to L.AS (66%; p < 0.001). These differences were related to increased student intake via a standard pass in L.AS (21% compared to 3.2% in PACES and 0.9% in PASS) (p < 0.001). In terms of geographical origin, the proportion of students residing in regions outside the University City area increased significantly in L.AS (11%) compared to PACES (1.7%) and PASS (3.3%) (p < 0.001). The mean number of parents from the white-collar and knowledge professional category was significantly higher in PACES (0.91) and PASS (1.06) compared to L.AS (0.80; p < 0.001). CONCLUSION: Students with a scientific background and who obtained highest honors in their high school diploma, remain the standard in PACES and PASS. Diversification of student profiles was achieved only within the L.AS gateway, which represented 42% of total second year admissions during the post-reform year. Student profile diversification was therefore a partially achieved objective and follow up studies of future promotions is needed to assess the medium and long-term impact of the reform. Particular attention should be paid to the future of these students who have different profiles between L.AS and PASS to determine whether these changes will have any impact in the quality of healthcare for the French population.

Démographie des chirurgiens-dentistes en région Centre-Val de Loire : opportunités et perspectives.

The Center Val de Loire region is particularly affected by the shortage of health professionals. The demographics of dentists are not immune to this situation and the retirement of a practitioner has become a real public health issue. For this purpose, bridges were created between the faculties of odontology of Nantes, Clermont-Ferrand and the Faculty of Medicine of Tours, to welcome short cycle students in Center Val de Loire region, to create a link with the liberal practitioners and to allow the students to confront the health issues of this territory.

[Dentistry demographics of Center Val de Loire region: Opportunities and prospects]. / Démographie des chirurgiens-dentistes en région Centre-Val de Loire : opportunités et perspectives.

The Center Val de Loire region is particularly affected by the shortage of health professionals. The demographics of dentists are not immune to this situation and the retirement of a practitioner has become a real public health issue. For this purpose, bridges were created between the faculties of odontology of Nantes, Clermont-Ferrand and the Faculty of Medicine of Tours, to welcome short cycle students in Center Val de Loire region, to create a link with the liberal practitioners and to allow the students to confront the health issues of this territory.

Hiatal hernia on thoracic computed tomography in pulmonary fibrosis.

Gastro-oesophageal reflux has long been suspected of implication in the genesis and progression of idiopathic pulmonary fibrosis (IPF). We hypothesised that hiatal hernia may be more frequent in IPF than in other interstitial lung disease (ILD), and that hiatal hernia may be associated with more severe clinical characteristics in IPF.We retrospectively compared the prevalence of hiatal hernia on computed tomographic (CT) scans in 79 patients with IPF and 103 patients with other ILD (17 scleroderma, 54 other connective tissue diseases and 32 chronic hypersensitivity pneumonitis). In the IPF group, we compared the clinical, biological, functional, CT scan characteristics and mortality of patients with hiatal hernia (n=42) and without hiatal hernia (n=37).The prevalence of hiatal hernia on CT scan at IPF diagnosis was 53%, similar to ILD associated with scleroderma, but significantly higher than in the two other ILD groups. The size of the hiatal hernia was not linked to either fibrosis CT scan scores, or reduction in lung function in any group. Mortality from respiratory causes was significantly higher among IPF patients with hiatal hernia than among those without hiatal hernia (p=0.009).Hiatal hernia might have a specific role in IPF genesis, possibly due to pathological gastro-oesophageal reflux.

Neutrophil proteases alter the interleukin-22-receptor-dependent lung antimicrobial defence.

Chronic obstructive pulmonary disease (COPD) is punctuated by episodes of infection-driven acute exacerbations. Despite the life-threatening nature of these exacerbations, the underlying mechanisms remain unclear, although a high number of neutrophils in the lungs of COPD patients is known to correlate with poor prognosis. Interleukin (IL)-22 is a cytokine that plays a pivotal role in lung antimicrobial defence and tissue protection. We hypothesised that neutrophils secrete proteases that may have adverse effects in COPD, by altering the IL-22 receptor (IL-22R)-dependent signalling.Using in vitro and in vivo approaches as well as reverse transcriptase quantitative PCR, flow cytometry and/or Western blotting techniques, we first showed that pathogens such as the influenza virus promote IL-22R expression in human bronchial epithelial cells, whereas Pseudomonas aeruginosa, bacterial lipopolysaccharide or cigarette smoke do not. Most importantly, neutrophil proteases cleave IL-22R and impair IL-22-dependent immune signalling and expression of antimicrobial effectors such as ß-defensin-2. This proteolysis resulted in the release of a soluble fragment of IL-22R, which was detectable both in cellular and animal models as well as in sputa from COPD patients with acute exacerbations.Hence, our study reveals an unsuspected regulation by the proteolytic action of neutrophil enzymes of IL-22-dependent lung host response. This process probably enhances pathogen replication, and ultimately COPD exacerbations.

Pharmacokinetics of Colistin Methansulphonate (CMS) and Colistin after CMS Nebulisation in Baboon Monkeys.

PURPOSE: The objective of this study was to compare two different nebulizers: Eflow rapid® and Pari LC star® by scintigraphy and PK modeling to simulate epithelial lining fluid concentrations from measured plasma concentrations, after nebulization of CMS in baboons. METHODS: Three baboons received CMS by IV infusion and by 2 types of aerosols generators and colistin by subcutaneous infusion. Gamma imaging was performed after nebulisation to determine colistin distribution in lungs. Blood samples were collected during 9 h and colistin and CMS plasma concentrations were measured by LC-MS/MS. A population pharmacokinetic analysis was conducted and simulations were performed to predict lung concentrations after nebulization. RESULTS: Higher aerosol distribution into lungs was observed by scintigraphy, when CMS was nebulized with Pari LC® star than with Eflow Rapid® nebulizer. This observation was confirmed by the fraction of CMS deposited into the lung (respectively 3.5% versus 1.3%).CMS and colistin simulated concentrations in epithelial lining fluid were higher after using the Pari LC star® than the Eflow rapid® system. CONCLUSIONS: A limited fraction of CMS reaches lungs after nebulization, but higher colistin plasma concentrations were measured and higher intrapulmonary colistin concentrations were simulated with the Pari LC Star® than with the Eflow Rapid® system.

Gastroesophageal reflux disease is a risk factor for severity of organizing pneumonia.

BACKGROUND: The link between organizing pneumonia (OP) and gastroesophageal reflux disease (GERD) is not well known. There is little evidence in the literature to establish a causal link between GERD and OP. OBJECTIVES: The aim of the study was to assess the hypothesis that OP is more severe when it is associated with GERD and that it leads to more frequent relapses. METHODS: In a retrospective study on 44 patients suffering from OP, we compared the clinical, radiological and histological characteristics of 2 groups, 1 composed of patients with GERD (n = 20) and the other of patients without GERD (n = 24). RESULTS: The GERD group was distinguished by a higher number of patients with migratory alveolar opacities on chest radiography and thoracic computerized tomography (14/20 vs. 9/24; p = 0.03 and 18/20 vs. 13/24; p = 0.01), greater hypoxemia [60 (42-80) vs. 70 (51-112) mm Hg; p = 0.03], greater bronchoalveolar lavage cellularity [0.255 (0.1-1.8) vs. 0.150 (0.05-0.4) g/l; p = 0.035] and more frequent relapses (14/20 vs. 9/24; p = 0.03). CONCLUSIONS: OP associated with GERD is more severe and results in more frequent relapses. Microinhalation of gastric secretions might induce lung inflammation leading to OP and relapse. We suggest that typical symptoms of GERD such as pyrosis should be investigated in OP.

Proteomic demonstration of the recurrent presence of inter-alpha-inhibitor H4 heavy-chain during aspergillosis induced in an animal model.

Invasive pulmonary aspergillosis remains a matter of great concern in oncology/haematology, intensive care units and organ transplantation departments. Despite the availability of various diagnostic tools with attractive features, new markers of infection are required for better medical care. We therefore looked for potential pulmonary biomarkers of aspergillosis, by carrying out two-dimensional (2D) gel electrophoresis comparing the proteomes of bronchial-alveolar lavage fluids (BALF) from infected rats and from control rats presenting non-specific inflammation, both immunocompromised. A bioinformatic analysis of the 2D-maps revealed significant differences in the abundance of 20 protein spots (ANOVA P-value<0.01; q-value<0.03; power>0.8). One of these proteins, identified by mass spectrometry, was considered of potential interest: inter-alpha-inhibitor H4 heavy-chain (ITIH4), characterised for the first time in this infectious context. Western blotting confirmed its overabundance in all infected BALF, particularly at early stages of murine aspergillosis. Further investigations were carried on rat serum, and confirmed that ITIH4 levels increased during experimental aspergillosis. Preliminary results in human samples strengthened this trend. To our knowledge, this is the first description of the involvement of ITIH4 in aspergillosis.

Validation of anatomical models to study aerosol deposition in human nasal cavities.

PURPOSE: Intranasal deposition of aerosols is often studied using in vitro nasal cavity models. However, the relevance of these models to predict in vivo human deposition has not been validated. This study compared in vivo nasal aerosol deposition and in vitro deposition in a human plastinated head model (NC1) and its replica constructed from CT-scan (NC2). METHODS: Two nebulizers (Atomisor Sonique® and Easynose®) were used to administer a 5.6 µm aerosol of (99m)Tc-DTPA to seven healthy volunteers and to the nasal models. Aerosol deposition was quantified by γ-scintigraphy in the nasal, upper nasal cavity and maxillary sinus (MS) regions. The distribution of aerosol deposition was determined along three nasal cavity axes (x, y and z). RESULTS: There was no significant difference regarding aerosol deposition between the volunteers and NC1. Aerosol deposition was significantly lower in NC2 than in volunteers regarding nasal region (p < 0.05) but was similar for the upper nasal cavity and MS regions. Mean aerosol distribution for NC1 came within the standard deviation (SD) of in vivo distribution, whereas that of NC2 was outside the in vivo SD for x and y axes. CONCLUSIONS: In conclusion, nasal models can be used to predict aerosol deposition produced by nebulizers, but their performance depends on their design.

Poly-L-Lysine compacts DNA, kills bacteria, and improves protease inhibition in cystic fibrosis sputum.

RATIONALE: Neutrophil serine proteases in cystic fibrosis (CF) lung secretions partially resist inhibition by natural and exogenous inhibitors, mostly because DNA impairs their control. Cationic polypeptides display the property of condensing DNA and retain antimicrobial properties. We hypothesized that DNA condensation by cationic polypeptides in CF sputum would result in a better control of CF inflammation and infection. OBJECTIVES: We examined whether poly-L-lysine would compact DNA in CF lung secretions and liquefy CF sputum, improve the control of extracellular proteases by exogenous inhibitors, and whether it displays antibacterial properties toward CF-associated bacteria. METHODS: We used fluorogenic methods to measure proteolytic activities and inhibition by protease inhibitors in whole sputum homogenates from patients with CF before and after treatment with poly-L-lysine. Antibacterial properties of poly-L-lysine were measured in bacterial cultures and in whole CF sputum. Poly-L-lysine toxicity was evaluated after aerosolization by histologic analysis, flow cytometry, and quantification of proinflammatory cytokines. MEASUREMENTS AND MAIN RESULTS: Poly-L-lysine compacts CF sputum DNA, generating a liquid phase that improves ciliary beating frequency at the lung epithelial surface, and allows the control of neutrophil elastase and cathepsin G by their natural inhibitors. It retains antimicrobial properties against Pseudomonas aeruginosa and Staphylococcus aureus at doses that induce no inflammation in the mouse lung after aerosol administration. CONCLUSIONS: Poly-L-lysine may be an alternative to dornase-α to liquefy sputum with added benefits because it helps natural inhibitors to better control the deleterious effects of extracellularly released neutrophil serine proteases and has the ability to kill bacteria in CF sputum.

Influence of DNA on the activities and inhibition of neutrophil serine proteases in cystic fibrosis sputum.

Uncontrolled proteolysis by neutrophil serine proteases (NSPs) in lung secretions is a hallmark of cystic fibrosis (CF). We have shown that the active neutrophil elastase, protease 3, and cathepsin G in CF sputum resist inhibition in part by exogenous protease inhibitors. This resistance may be due to their binding to neutrophil extracellular traps (NETs) secreted by the activated neutrophils in CF sputum and to genomic DNA released from senescent and dead neutrophils. Treating CF sputum with DNase dramatically increases its elastase activity, which can then be stoichiometrically inhibited by exogenous elastase inhibitors. However, DNase treatment does not increase the activities of protease 3 and cathepsin G, indicating their different distribution and/or binding in CF sputum. Purified blood neutrophils secrete NETs when stimulated by the opportunistic CF bacteria Pseudomonas aeruginosa and Staphylococcus aureus. The activities of the three proteases were unchanged in these conditions, but subsequent DNase treatment produced a dramatic increase in all three proteolytic activities. Neutrophils activated with a calcium ionophore did not secrete NETs but released huge amounts of active proteases whose activities were not modified by DNase. We conclude that NETs are reservoirs of active proteases that protect them from inhibition and maintain them in a rapidly mobilizable status. Combining the effects of protease inhibitors with that of DNA-degrading agents could counter the deleterious proteolytic effects of NSPs in CF lung secretions.

The clinical course of interstitial lung disease in an adult patient with an ABCA3 homozygous complex allele under hydroxychloroquine and a review of the literature.

OBJECTIVE: The gene mutations responsible for ABCA3 protein deficiency are involved in respiratory distress of the newborn and much more rarely in adult interstitial lung diseases (ILD). An adult patient homozygous for a complex allele encompassing the p.Ala1027Pro likely pathogenic mutation and the p.Gly974Asp variation was followed for a late-onset and fibrotic ILD. The evolution was marked by progressive clinical and functional degradation despite corticosteroid pulses. The patient, who was first registered on the list for lung transplantation, was improved quickly and persistently for at least 6.5 years with hydroxychloroquine treatment, allowing removal from the transplant list.

The airways, a novel route for delivering monoclonal antibodies to treat lung tumors.

PURPOSE: Lung cancer is the leading cause of cancer-related death worldwide. The efficacy of current systemic treatments is limited, with major side effects and only modest survival improvements. Aerosols routinely used to deliver drugs into the lung for treating infectious and inflammatory lung diseases have never been used to deliver monoclonal antibodies to treat lung cancer. We have shown that cetuximab, a chimeric anticancer anti-EGFR mAb, is suitable for airway delivery as it resists the physical constraints of aerosolization, and have evaluated the aerosol delivery of cetuximab in vivo. METHODS: We developed an animal model of lung tumor sensitive to cetuximab by injecting Balb/c Nude mice intratracheally with A431 cells plus 10 mM EDTA and analyzed the distribution, pharmacokinetics and antitumor efficacy of cetuximab aerosolized into the respiratory tract. RESULTS: Aerosolized IgG accumulated durably in the lungs and the tumor, but passed poorly and slowly into the systemic circulation. Aerosolized cetuximab also limited the growth of the mouse tumor. Thus, administering anticancer mAbs via the airways is effective and may limit systemic side effects. CONCLUSION: Delivery of aerosolized-mAbs via the airways deserves further evaluation for treating lung cancers.

Pharmacokinetics of colistin after nebulization or intravenous administration of colistin methanesulphonate (Colimycin®) to cystic fibrosis patients.

OBJECTIVES: Colistin, administered as the prodrug colistin methanesulphonate (CMS), is an antibiotic frequently administered as aerosol in cystic fibrosis (CF) patient. Our aim was to assess the plasma PK of colistin in CF patients treated with CMS administered intravenously or as aerosol and to compare these results with those previously reported in healthy volunteers. METHODS: Six CF patients were included, CMS and colistin concentrations were measured in plasma, urine and sputum. Either after single intravenous administration of 2 Million International Unit (MIU) or after repeated nebulizations of 2 MIU of CMS. PK of CMS and colistin were assessed by a mixed effect modeling approach. RESULTS: Renal clearance of CMS was lower in CF patients compared to that previously reported in healthy volunteers (64.3 mL/min (RSE = 15%) vs. 103 mL/min (RSE = 8%)). However, apparent clearance of colistin was higher in CF patients compared to healthy volunteers (124 mL/min (RSE = 13%) vs. 48.7 mL/min (RSE = 15%)), resulting in reduced systemic exposure to colistin (dose normalized AUC (2 MIU) of 7.4 h.mg/L/MIU vs. 11.2 h.mg/L/MIU). After repeated nebulizations, colistin concentrations were very low in plasma (<0.21 mg/L). CONCLUSIONS: Although our study suggests a lower median dose normalized colistin plasma concentrations in CF patients compared with healthy controls, this difference was not significant and a larger study is needed to substantiate this.

Desquamative interstitial pneumonia induced by metal exposure. A case report and literature review.

BACKGROUND: Forms of interstitial pneumonia secondary to exposure to an air-contaminant are varied and so far, insufficiently described. OBJECTIVES/METHODS: We report here a case of a 57-year-old patient managed in our department for the exploration of MRC grade 2 dyspnoea and interstitial pneumonia. He mentioned multiple occupational and domestic exposures such as hens' excrements, asbestos and metal particles; he also had a previous history of smoking. RESULTS: High-resolution computed tomography showed ground glass opacities predominating in posterior territories and surrounding cystic lesions or emphysematous destruction. The entire etiological assessment revealed only macrophagic alveolitis with giant multinucleated cells on the bronchoalveolar lavage. A surgical lung biopsy allowed us to refine the diagnosis with evidence of desquamative interstitial pneumonia and pulmonary granulomatosis. Finally, the analysis of the mineral particles in the biopsy revealed abnormally high rates of Zirconium and Aluminium. We were therefore able to conclude to a desquamative interstitial pneumonia associated with pulmonary granulomatosis linked to metal exposure (Aluminium and Zirconium). The clinical, functional and radiological evolution was favorable after a systemic corticosteroid treatment with progressive decay over one year. CONCLUSION: This presentation reports the first case to our knowledge of desquamative interstitial pneumonitis related to exposure to Zirconium and the third one in the context of Aluminium exposure. The detailed analysis of the mineral particles present on the surgical lung biopsy allows for the identification of the relevant particle to refine the etiological diagnosis, to guide the therapeutic management and to give access to recognition as an occupational disease. (Sarcoidosis Vasc Diffuse Lung Dis 2020; 37 (1): 79-84).

Feasability of human endobronchial imaging with a linear-array ultrasound catheter.

PURPOSE: To explore the feasability of imaging lung masses with a novel endobronchial linear-array transducer. METHOD: We used a linear-array transducer of 7 F (2.3 mm in diameter) operating at a center frequency of 10 MHz for endobronchial imaging. We used the probe in 20 subjects with suspected lung cancer to identify and measure the tumor; to asses the tumor's sonographic characteristics, bronchial wall invasion, and presence of lymph nodes; to guide a transbronchial needle aspiration (TBNA); and to evaluate potential side effects. RESULTS: In all patients, the tumor was identified and the relationship with the bronchial wall correctly evaluated through the depiction of a 3-layer wall pattern. Bronchial wall invasion was suspected in 5 patients, small adjacent lymph nodes were detected in 3 patients, and a small pleural effusion was observed close to the lung lesion in 2 patients. The linear-array probe allowed the guidance of successful TBNA with no complications. CONCLUSION: This feasibility study shows that the prototype probe can be used to depict pulmonary lesions and to guide biopsy nodes. Larger series are needed to validate its usefulness in clinical work-ups and patients management.